1. Field of the Invention
The present invention relates generally to medical devices and procedures and, more particularly, to apparatuses and methods for predicting hormone levels in patients after removal of portions of hormone-secreting glands.
2. Description of Related Art
Primary hyperparathyroidism, which is the result of the hypersecretion of parathyroid hormone (PTH) by abnormal parathyroid glands, is relatively common, with an overall incidence of approximately 1 in 1000. The incidence of disease increases with age and is more common in women. Secondary hyperparathyroidism is also the result of excess parathyroid hormone production. The parathyroid hormone secretion, however, is appropriate in secondary hyperparathyroidism and is in response to low serum calcium, as a consequence, for example, of chronic renal disease. Familial hypocalciuric hypercalcemia is an autosomal dominant genetic disorder, and it is important to recognize because these patients do not benefit from parathyroidectomy. The genetic defect is in the calcium receptor, which makes it less sensitive to calcium and consequently leads to increased parathyroid hormone secretion. The other causes of hypercalcemia include various diet and drug induced causes, as well as several miscellaneous endocrine and inflammatory disorders.
Most of the symptoms are predictable based on the known function of parathyroid hormone. The excess parathyroid hormone causes accelerated bone loss, which can lead to bone demineralization and pathologic bone fractures. Kidney stones are another common manifestation of the disease. Although parathyroid hormone increases the renal reabsorption of calcium from urine, the overall urinary excretion of calcium is still increased because of the elevated serum calcium. Excess calcium in the urine can form a complex with phosphate and form kidney stones. In addition to these predicted manifestations, there are also numerous vague constitutional symptoms, such as gastrointestinal discomfort, and various mental status changes, such as depression and anxiety. In the past, most patients were not diagnosed until they presented signs and symptoms. Since the advent of chemistry screening panels, the majority of patients are now diagnosed earlier in their disease by an elevated serum calcium and are often asymptomatic.
The parathyroid glands are pea size glands located posterior to the thyroid gland. Typically there are 4 glands, but approximately 2 to 6% of individuals have more than 4 glands, and sometimes as many as 12 glands. Parathyroid glands can also be located in atypical or ectopic locations in about 15% of patients. Embryologically the parathyroid glands are derived from tissue in the upper part of the neck that later descends to their adult locations. Ectopic glands can be found anywhere from behind the ear to all the way in to the chest, for those glands that have over migrated. Approximately in 80-85% of cases, primary hyperparathyroidism is caused by a solitary benign parathyroid adenoma. Parathyroid adenomas are a clonal expansion of a cell that has an altered set point for regulating calcium that results in the over production of parathyroid hormone relative to the level of serum calcium. Less than 1% of parathyroid adenomas are malignant. The remaining cases of hyperparathyroidism are caused by multiple adenomas (2-3%) or by a diffuse enlargement or hyperplasia of all of the parathyroid glands (12-15%). The hyperplasia of parathyroid glands is often associated with Multiple Endocrine Neoplasia, a genetic disorder that is characterized by adenomas in multiple endocrine glands, such as the pituitary, parathyroid, adrenal and pancreas.
The overproduction of parathyroid hormone, which is synthesized by the parathyroid gland and is the key hormone that regulates calcium metabolism, is a relatively common disease referred to as hyperparathyroidism. Adenomas of the parathyroid gland often cause the overproduction of parathyroid hormone. The elevated serum calcium caused by the excess parathyroid hormone can result in various constitutional symptoms and can account for the formation of kidney stones and the loss of bone density in patients with hyperparathyroidism. The treatment of choice for hyperparathyroidism is surgical removal of any parathyroid adenomas.
There are approximately 180,000 parathyroidectomies performed annually worldwide. The goal of the surgery is the complete removal of the parathyroid hormone hypersecreting glands. Patients with solitary adenomas are cured after the removal of the one abnormal gland. Patients with diffuse hyperplasia of 4 glands are usually treated by the excision of approximately 3.5 glands. Residual tissue is left behind to prevent the development of hypocalcemia. The main challenge in the surgical treatment of hyperparathyroidism is the identification of the parathyroid glands that are over producing parathyroid hormone.
Recent radiologic techniques have improved the pre-operative localization of adenomas, but they are not fully reliable. During surgery, the direct visual inspection of the size and color of the gland can also be helpful, but it is not fully reliable for identifying abnormal parathyroid glands. Histologic examination, at the time of surgery, of any excised tissue is usually helpful for distinguishing normal from abnormal parathyroid glands. Parathyroid adenomas, however, can not be readily distinguished from hyperplasia by histology. This is an important limitation, because even if the removed gland is found to be abnormal, one can not exclude the possibility that the remaining glands are hyperplastic. In addition, patients with parathyroid adenomas that have multiple adenomas can be missed by performing just a histologic exam of 1 gland. Because of these problems, all 4 glands are usually inspected grossly during surgery and often biopsied for histologic examination. This increases the time and expense of the surgery and also increases the chance for morbidity from the procedure, the most important of which is damage to the recurrent laryngeal nerve and subsequent vocal cord dysfunction. Despite the extra precaution of inspecting all the parathyroid glands, as many as 10-15% of patients, depending on the experience of the surgeon, are not cured the first time by surgery. Treatment failures occur, in part, because of the difficulty in identifying and recognizing abnormal glands, and because of ectopic and supernumerary parathyroid glands.
In performing surgical procedures for excising parathyroid adenomas, surgeons need to be able to quickly determine whether all of the parathyroid adenomas have been removed. Because all of the signs and symptoms of hyperparathyroidism are the result of excess parathyroid hormone, the intraoperative monitoring of the drop in serum parathyroid hormone following the excision of abnormal parathyroid glands can be used to confirm the removal of the parathyroid adenoma.
One device for facilitating monitoring of the drop in serum parathyroid hormone is an intraoperative assay for the quantitative determination of parathyroid hormone levels, referred to as the QuiCk-IntraOperative.TM. Intact PTH, and developed and sold by Nichols Institute Diagnostics of San Juan Capistrano, Calif. By facilitating the determination of parathyroid hormone levels in human serum and Ethylenediaminetetraacetic Acid (EDTA) treated samples, the intraoperative assay provides the surgeon with a means for quickly determining whether all of the parathyroid adenomas have been removed. Another similar product is the Nichols Advantage.RTM. Chemiluminescence Specialty System, also sold by Nichols Institute Diagnostics and described, for example, at http://www.nicholsdiag.com.
Since the half-life of parathyroid hormone is approximately 3 minutes, the removal of the abnormal gland can be assessed by a drop of serum parathyroid hormone within 5 to 10 minutes after the resection of the tissue. Because the secretion of parathyroid hormone by the remaining normal glands are suppressed by the elevated serum calcium, the level of parathyroid hormone quickly drops into either the normal or below normal range after the surgery. The intraoperative assay is used to detect whether the parathyroid hormone concentration has decreased by more than 50% within 5 minutes post resection, indicating that the patient is cured. A primary means of intraoperatively determining whether a complete surgical removal of multiple parathyroid adenomas, for example, has occurred has been the measurement of the drop in serum parathyroid hormone. The prior art to Applicants'knowledge has proposed no other satisfactory means for intraoperatively confirming the surgical removal of parathyroid adenomas.
The conventional intraoperative assay, which requires the measurement of the parathyroid hormone concentration at 5 minutes post resection, can be extremely time-restrictive. The choice of the 5 minute time point is arbitrary, but the value for interpreting the result is only valid for the 5 minute time point. The requirements of surgery can render collection of the serum at precisely the 5 minute time point difficult. The prior-art intraoperative assay does not provide recommendations on how to interpret the data when the serum is collected earlier or later than the 5 minute time point.
Moreover, the half-life of the decay of the parathyroid hormone in patients can vary as much as five-fold, which if not accounted for can significantly affect the interpretation of the data and can potentially lead to false positive and false negative diagnoses. It can be difficult using the prior-art intraoperative assay to directly translate the percent drop in parathyroid hormone into how much residual parathyroid hormone secreting tissue is present after the surgery. In addition, it can be difficult to translate the percent drop in parathyroid hormone at 5 minutes to the expected level of PTH when it reaches equilibrium. Both of these concerns can be particularly important, for example, in patients with multiple adenomas/hyperplasia. If the parathyroid hormone result is not correctly interpreted, incomplete removal of the adenomas or excess removal of parathyroid tissue can occur.